Natural products serve as critical drugs or drug precursors with broad pharmaceutical application, including serving as the most effective antibiotics. The widespread and rapid evolution of antibiotic-resistance in pathogenic microbes makes the discovery of novel therapeutics to treat infectious diseases of urgent importance. Despite this critical need, small molecule discovery has decreased substantially in recent decades and the pipeline of new antibiotics is rapidly diminishing. The broad goals of this project are to discover novel antibiotics with high therapeutic potential by identify new natural products from insect associated Actinobacteria (aim 1), using next-generation sequencing technology and bioinformatics to help discover novel compounds from symbiotic microbes (aim 2), and evaluating the natural products discovered in SAI and SA2 for their therapeutic potential (aim 3). Through its direct integration with the multidisciplinary team in the center, the work proposed holds the promise to generate numerous new drug leads with therapeutic potential, result in a new paradigm in drug discovery, and, by translation, to impact the treatment of drug-resistant infectious diseases on a global scale.